title: Functional dissection of protein domains involved in the immunomodulatory properties of PE_PGRS33 of Mycobacterium tuberculosis.
abstract: PE_PGRSs are a large family of proteins identified in Mycobacterium tuberculosis complex and in few other pathogenic mycobacteria. The PE domain of PE_PGRS33 mediates localization of the protein on the mycobacterial cell surface, where the PGRS domain is available to interact with host components. In this study, PE_PGRS33 and its functional deletion mutants were expressed in M. smegmatis, and in vitro and in vivo assays were used to dissect the protein domains involved in the immunomodulatory properties of the protein. We demonstrate that PE_PGRS33-mediated secretion of TNF-α by macrophages occurs by extracellular interaction with TLR2. Our results also show that while the PGRS domain of the protein is required for triggering TNF-α secretion, mutation in the PE domain affects the pro-inflammatory properties of the protein. These results indicate that PE_PGRS33 is a protein with immunomodulatory activity and that protein stability and localization on the mycobacterial surface can affect these properties.
authors.affiliation: Institute of Microbiology, Universitá Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Zumbo
authors.forename: Ivana
authors.initials: I
authors.lastname: Palucci
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cascioferro
authors.forename: Michela
authors.initials: M
authors.lastname: Sali
authors.forename: Marcello
authors.initials: M
authors.lastname: Ventura
authors.forename: Pamela
authors.initials: P
authors.lastname: D'Alfonso
authors.forename: Raffaella
authors.initials: R
authors.lastname: Iantomasi
authors.forename: Gabriele
authors.initials: G
authors.lastname: Di Sante
authors.forename: Francesco
authors.initials: F
authors.lastname: Ria
authors.forename: Maurizio
authors.initials: M
authors.lastname: Sanguinetti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fadda
authors.forename: Riccardo
authors.initials: R
authors.lastname: Manganelli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Delogu
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D005110:Extracellular Space; D005260:Female; D015870:Gene Expression; D056747:Immunomodulation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D013163:Splenomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D008565:Membrane Proteins; C440642:PE-PGRS protein, Mycobacterium; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha
keywords: Mycobacterium tuberculosis; PE_PGRS; TLR2